Abstract Tick borne pathogens are important health concerns worldwide due to increasing numbers of diseases caused by these microorganisms and also due to emergent/re-emerging diseases incidence. Many studies have shown the intricacy of tick physiology and salivary components, which directly affect the success of disease transmission. During attachment to the host for and feeding days or weeks, these arthropods induce significant inflammation at the skin site of tick feeding as demonstrated in our and other researchers' studies. Interestingly, proteins in saliva of different species of ticks have the properties of inducing many of the host immune pathways, reducing or activating mechanisms of host defense. Depending on the pathogen carried by ticks, the saliva of ticks could favor infection or host protection; however, the effect is usually to achieve adaptation. Severe ehrlichial infection causes a dysregulation in the inflammatory host response that is associated with tissue damage and increased pro-inflammatory cytokines. The inflammasome pathway is implicated in modulation of the lethal imbalance. Sialostatins in tick saliva cause potential inhibition of host NLRs and caspases; however, there is a lack of knowledge of the effect of tick attachment and feeding on activation of inflammasome during transmission of ehrlichial pathogen. All studies evaluate highly reductionistic individual cell responses to tick saliva, or the effects of a single salivary protein in the skin site of bacterial inoculation, and so forth. We propose to evaluate the effects of a physiological mode of ehrlichial transmission by its tick vector to understand the early host response involving the inflammasome pathway. Our central hypothesis is that tick transmission of ehrlichiae modulates NLRP3 inflammasome pathway activation with increased inflammatory response and recruitment of monocytes-macrophages to the infection site, favoring bacterial dissemination and disease progression. In this proposal, we will characterize the dynamics of NLRP3- caspase-1 inflammasome activation, monocyte-macrophage recruitment and bacterial dissemination induced by ehrlichiae transmitted by ticks (Aim 1), and identify the role of the mode of infection on the modulation of inflammasome activation during early ehrlichial disease (Aim 2). After accomplishing the aims of this project, we will be able to determine the effects of EML transmitted by I. scapularis in activation of the inflammasome complex and the importance of the mode of infection on this process. This study is timely as it addresses a member of a genus of emerging pathogens and will offer new insights into disease pathogenesis and potential for immunomodulatory therapy.